Optical isomers of 4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide

ABSTRACT

The resolution of racemic 4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide into the optically active (+) and (-) isomers is disclosed.

This is a division of application Ser. No. 914,833, filed June 12, 1978, now abandoned, which is a continuation-in-part of our copending application Ser. No. 658,989 filed Feb. 18, 1976. ABN which is a continuation-in-part application of copending application Ser. No. 518,125 filed Oct. 25, 1974, ABN which was a continuation application of Ser. No. 340,417 filed Mar. 12, 1973, now abandoned, which was a continuation-in-part of Ser. No. 240,840 filed Apr. 30, 1972, now abandoned.

The present invention relates to resolving optical isomers of 4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide of the following formula: ##STR1## to the optical isomers thereby obtained, the pharmaceutically acceptable acid addition salts thereof, and to a method for the use of such isomers.

4-Amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide possesses valuable therapeutic properties as in anti-emetic and has minimal side effects with a notable absence of cataleptic properties.

The optically active (+) and (-) isomers of the present invention possess useful pharmacological and therapeutic properties as anti-emetics and anti-cataleptics in some ways quite different from those of the corresponding racemic mixture.

It is therefore an object of the present invention to provide (+)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide substantially free from its optical antipode. A further object is to provide a method for the separation of (+)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide from (-)-4-amino-N-(1-cyclohexyl-3-pyrrolidiny)-N-methylbenzamide. A still further object is to provide pharmaceutical compositions containing as active ingredient the respective (+) and (-) isomers and methods for their use. Additional objects will become apparent from the description which follows and the appended claims.

We have found that the levo-rotary form of 4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide can be readily obtained from the racemic form using (-)-malic acid and that the dextro-rotary form can be readily obtained after separation of (-)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide malate by treating the mother liquors with (+)-malic acid.

The free bases of the levo-rotary and the dextro-rotary forms of 4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide can be obtained by basifying an aqueous solution of the respective salt with sodium hydroxide and extracting with chloroform. The chloroform solution is then concentrated in vacuo leaving the free base oil which can be crystallized and then recrystallized from isopropyl ether. Alternately, the free base oil may be distilled in a molecular still and then recrystallized from isopropyl ether.

The optically active (+) and (-) isomers of 4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide in crystalline and substantially pure form and substantially free one from the other are bases which react with pharmaceutically acceptable organic and inorganic acids to produce the corresponding acid addition salts, which have the same activity and are useful for the same purposes as the free bases.

Among the pharmaceutically acceptable acids which can be used to form such salts but not limited thereto are hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulfamic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, benzoic acid, tartaric acid, p-aminobenzoic acid and succinic acid.

The acute toxicities of the ±-racemate, the (+)-isomer and the (-)-isomer were conducted with the fumarate salts and probit analysis (Finney, D. J., Statistical Methods in Biological Assay, Hafner Pub. Co., N.Y., 2nd. Ed., 1964) was employed for the statistical treatment of the mortality data. The data are summarized in Table I.

                  TABLE I                                                          ______________________________________                                                     LD.sub.50 mg/kg (95% Confidence Limits).sup.a                      Compound  Animal    I.P.         P.O.                                          ______________________________________                                         ± racemate                                                                            mouse    90.2 (84.5-96.4)                                                                             181 (166-199)                                 (-)-isomer                                                                               mouse   103.0 (96.0-110.0)                                                                            241 (220-263)                                 (+)-isomer                                                                               mouse   126 (115-139)  267 (233-313)                                 ± racemate                                                                            rat     111 (103-120)  305 (272-392)                                 (-)-isomer                                                                               rat     116 (107-130)  410 (357-500)                                 (+)-isomer                                                                               rat     147 (134-222)  499 (322-593)                                 ______________________________________                                          .sup.a Expressed as free base                                            

The anti-emetic properties of the fumarate salts were established in dogs using a modification of the anti-apomorphine methods of Chen and Ensor, J. Pharmac. Exp. Ther. 98, 245-250 (1950) and of Leonard et al., J. Pharmac. Exp. Ther. 154, 339-345 (1966) and the ED₅₀ was calculated by the method of Goldstein (Biostatistics, An Introductory Text, pg. 156-161, The MacMillan Co., N.Y., 1964). The data are summarized in Table II.

                  TABLE II                                                         ______________________________________                                                               ED.sub.50 mg/kg, s.c..sup.a                              Compound    Animal    (95% Confidence Limits)                                  ______________________________________                                         ± racemate                                                                              dog       0.25 (0.19-0.31)                                         (-)-isomer  dog       0.09 (0.05-0.17)                                         (+)-isomer  dog       no significant anti-                                                           apormorphine activity                                    ______________________________________                                          .sup.a Expressed as free base                                            

The procedure used for determing cataleptic effects of the fumarate salts was based on that of Tedeschi et al., Arch. Int. Pharmacodyn. Ther. 122, 129-143 (1959). The data are summarized in Table III.

                  TABLE III                                                        ______________________________________                                                      Summary.sup.a                                                     Compound  Animal   IP (mg/kg) PO (mg/kg)                                       ______________________________________                                         ± racemate                                                                            rat      NSE to 100.sup.b,c                                                                        NSE to 200                                       (-)-isomer                                                                               rat      ED.sub.50 > 100.sup.c                                                                     ED.sub.50 80 (estimated)                         (+)-isomer                                                                               rat      NSE to 100.sup.c                                                                          NSE to 200                                       ______________________________________                                          .sup.a Expressed as free base                                                  .sup.b NSE = no significant cataleptic effect in doses up to indicated         amount                                                                         .sup.c Neurotoxic dose level evidenced by seizures in test animals       

(+)-4-Amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide is useful in reducing the cataleptic side effects of known therapeutically effective drugs such as chlorpromazine [2-chloro-10-(3-dimethylaminopropyl)phenothiazine] and metoclopramide (N-diethylaminoethyl 2-methoxy-4-amino-5-chlorophenylcarboxamide). The effectiveness is shown in Tables IV and V. In each test the rat was administered a 100% effective cataleptic dose of the test drug followed one hour later by an effective dose of (+)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide.

                                      TABLE IV                                     __________________________________________________________________________     Effects on Chlorpromazine-Induced Catalepsy                                            Treatment                                                              Initial After  Percent of Rats Cataleptic at:                                  Treatment                                                                              One Hour                                                                              (hours after initial treatment)                                 IP      IP     0.5                                                                               1.0                                                                               1.5                                                                               2.0                                                                               3.0                                                                               4.0                                                                               5.0                                                                               6.0                                        __________________________________________________________________________     saline  saline 0  0  0  0  0  0  0  0                                          10 ml/kg                                                                               10 ml/kg                                                               saline  (+)-isomer                                                                            0  0  0  0  0  17 17 0                                          10 ml/kg                                                                               25 mg/kg                                                               Chlorpromazine                                                                         saline 100                                                                               100                                                                               100                                                                               100                                                                               100                                                                               100                                                                               100                                                                               100                                        4 mg/kg 10 mg/kg                                                               Chlorpromazine                                                                         (+)-isomer                                                                            100                                                                               100                                                                               50 33 33 50 100                                                                               67                                         4 mg/kg 25 mg/kg                                                               __________________________________________________________________________

                                      TABLE V                                      __________________________________________________________________________     Effects on Metoclopramide-Induced Catalepsy                                             Treatment                                                             Initial  After  Percent of Rats Cataleptic at:                                 Treatment                                                                               One Hour                                                                              (hours after initial treatment)                                IP       IP     0.5                                                                               1.0                                                                               1.5                                                                               2.0                                                                               3.0                                                                               4.0                                                                               5.0                                                                               6.0                                                                               7.0                                    __________________________________________________________________________     saline   saline 0  0  0  0  0  0  0  0  0                                      10 ml/kg 10 mg/kg                                                              Metoclopramide                                                                          saline 100                                                                               100                                                                               100                                                                               100                                                                               100                                                                               100                                                                               100                                                                               100                                                                               --                                     40 mg/kg 10 mg/kg                                                              Metoclopramide                                                                          (+)-isomer                                                                            100                                                                               100                                                                               100                                                                               88 88 100                                                                               100                                                                               100                                                                               100                                    40 mg/kg 12.5 mg/kg                                                            Metoclopramide                                                                          (+)-isomer                                                                            100                                                                               100                                                                               100                                                                               75 38 75 88 88 --                                     40 mg/kg 25 mg/kg                                                              Metoclopramide                                                                          (+)-isomer                                                                            88 88 25 13 38 38 88 88 88                                     40 mg/kg 40 mg/kg                                                              Metoclopramide                                                                          (+)-isomer                                                                            100                                                                               100                                                                               13 13 25 25 75 88 75                                     40 mg/kg 50 mg/kg                                                              __________________________________________________________________________

The invention is illustrated by the following examples without being limited thereto.

EXAMPLE 1 4-Amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide Cyclohexanesulfamate

4-Nitro-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide was prepared from 15 g. (0.085 mole) of 1-cyclohexyl-3-methylaminopyrrolidine and 15 g. (0.08 mole) p-nitrobenzoyl chloride. The 4-nitro-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide was converted to the fumarate salt (8.4 g., 24%) by precipitation with fumaric acid from isopropanol-isopropyl ether. The fumarate salt was dissolved in 95% ethanol and hydrogenated at three atmospheres of hydrogen over Raney Nickel for about two hours. The mixture was filtered, the filtrate concentrated and the residue partitioned between dilute sodium hydroxide and chloroform. The chloroform layer was dried and concentrated and the residue treated with hexamic acid in isopropanol-isopropyl ether. Recrystallization from the same solvent gave 5.2 g. (13.5% overall) of the salt melting 196°-199° C.

Analysis: Calculated for C₂₄ H₄₀ N₄ O₄ S: C,59.97; H,8.39; N,11.66. Found: C,59.84; H,8.39; N,11.55.

EXAMPLE 2 (-)-4-Amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide Malate

An ethanol solution containing 20.0 g. (0.067 mole) of 4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide was treated with 4.94 g. (0.037 mole) of (-)-malic acid and the solution was refrigerated overnight. The crystalline material which separated (m.p. 147°-157° C.) was recrystallized twice from ethanol to give 5.0 g. crystals which melted at 161°-163° C.

Rotation [α]_(D) ³⁰ :-22.65 (water).

Analysis: Calculated for C₂₂ H₃₃ N₃ O₆ : C,60.67; H,7.64; N,9.65. Found: C,60.25; H,7.61; N,9.64.

EXAMPLE 3 (+)-4-Amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methyl benzamide Malate

The mother liquor and filtrates for Example 2 were combined and concentrated. The residue was partitioned between chloroform and dilute sodium hydroxide. The chloroform was concentrated and the residue in ethanol solution was treated with 2 g. of (-)-malic acid and placed in the refrigerator overnight. The resulting solid was filtered and discarded. The filtrate was concentrated and partitioned between chloroform and dilute sodium hydroxide. The chloroform was concentrated and the residue treated with 2 g. of (+)-malic acid in ethanol. The resulting crystals were recrystallized from ethanol. Yield 2.2 g., m.p. 161°-163° C.

Rotation [α]_(D) ³⁰ :+24.81 (water).

Analysis: Calculated for C₂₂ H₃₃ N₃ O₆ : C,60.67; H,7.64; N,9.65. Found: C,60.41; H,7.66; N,9.55.

EXAMPLE 4 (-)-4-Amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methyl benzamide Fumarate

An aqueous solution containing 3.9 g. (0.0094 mole) of (-)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide malate was made basic with sodium hydroxide and the basic solution was extracted with chloroform, the chloroform solution was dried over sodium sulfate and concentrated in vacuo. The thick oily residue is the free base, (-)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide fumarate. The residue was dissolved in ethanol, 1.2 g. (0.01 mole) of fumaric acid added and the solution refrigerated. The fumarate salt which separated weighed 3.3 g. and melted at 205°-207° C.

Rotation [α]_(D) ³⁰ :-13.89 (methanol).

Analysis: Calculated for C₂₂ H₃₁ N₃ O₅ : C,63.29; H,7.48; N,10.06. Found: C,63.12; H,7.47; N,10.11.

EXAMPLE 5 (+)-4-Amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methyl benzamide Fumarate

An aqueous solution of 2.2 g. (0.005 mole) of (+)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide malate was made basic using sodium hydroxide and the basic solution was extracted with chloroform. The dried chloroform solution was concentrated in vacuo. The thick oily residue is the free base, (+)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide. The residue was treated with a solution of 0.6 g. (0.005 mole) of fumaric acid in ethanol-methanol. The fumarate salt which separated weighed 1.6 g. and melted at 204°-206° C.

Rotation [α]_(D) ³⁰ :+12.72 (methanol).

Analysis: Calculated for C₂₂ H₃₁ N₃ O₅ : C,63.29; H,7.48; N,10.06. Found: C,63.71; H,7.39; N,9.85.

EXAMPLE 6 (-)-4-Amino-N-(1-cyclohexyl-3-pyrrolidinyl-N-methyl benzamide

Three grams (0.007 mole) of (-)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide fumarate was partitioned between chloroform and dilute sodium hydroxide. The chloroform solution was dried with anhydrous sodium sulfate and concentrated in vacuo on a steam bath. The residue was distilled on a molecular still at 0.1 mm pressure and 190° C. The distillate was crystallized from isopropyl ether. Yield 1.5, m.p. 106°-108° C.

Rotation [α]_(D) ²⁵ :-46.81 (chloroform).

Analysis: Calculated for C₁₈ H₂₇ N₃ O: C,71.72; H,9.03; N,13.94. Found: C,71.97; H,9.08; N,13.85.

EXAMPLE 7 (+)-4-Amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methyl benzamide

Two grams (0.005 mole) of (+)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide fumarate was partitioned between chloroform and dilute sodium hydroxide. The chloroform solution was dried with anhydrous sodium sulfate and concentrated. On standing overnight the oil crystallized and was recrystallized from isopropyl ether. Yield 1.3 g., m.p. 106.5°-108° C.

Rotation [α]_(D) ²⁵ :+48.55 (chloroform).

Analysis: Calculated for C₁₈ H₂₇ N₃ O: C,71.62; H,9.03; N,13.94. Found: C,71.77; H,9.08; N,13.96.

The pharmaceutical compositions of this invention comprise the anti-emetic (-)-isomer and the anti-cataleptic (+)-isomer of Formula I as the active ingredient in an amount to provide said activity. The compositions contain 1.0 mg. to 100 mg. of the respective isomer per unit dose. Preferably, the compositions contain from about 5 mg. to 100 mg. of the active ingredient, advantageously from about 5 mg. to about 50 mg. per unit dose.

The pharmaceutical carrier employed in the composition can be either solid or liquid. Exemplary of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. Exemplary of liquid carriers are vegetable oils and water. Similarly, the carrier or diluent may include a sustained release material such as glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used the composition can be tableted or prepared as a powder, a troche, a lozenge or a suppository. Gelatin capsules containing the medicament can also be prepared. If a liquid carrier is used, the composition can be in the form of a soft gelatin capsule, a liquid suspension of a syrup. Parenteral dosage forms are obtained by dissolving a water-soluble salt of the active ingredient in water or saline solution in a concentration such that 1 cc. of the solution contains from 1.0 mg. to 25 mg. of active ingredient. The solution can then be filled into single or multiple dose ampules.

The method in accordance with this invention comprises administering internally to warm blooded animals including human beings (+)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide to control catalepsy and (-)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide to control emesis or a nontoxic organic or inorganic acid addition salt thereof, preferably with a nontoxic pharmaceutical carrier such as described above. The active isomer is administered orally or parenterally in repeated doses until satisfactory response is obtained. The daily dosage is from about 10 mg. to about 300 mg. of active medicament, advantageously from about 5 mg. to 50 mg.

Various modifications and equivalents will be apparent to one skilled in the art, and may be made in the compounds, compositions of the present invention without departing from the spirit or scope thereof, and it is to be understood that the invention is to be limited only by the scope of the appended claims. 

What is claimed is:
 1. A method for controlling emesis in warm blooded animals which comprises administering internally to said animals in need thereof an effective amount of (-)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide malate in the presence of a pharmaceutical carrier therefor.
 2. A method for controlling emesis in warm blooded animals which comprises administering internally to said animals in need thereof an effective amount of (-)-4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide fumarate in the presence of a pharmaceutical carrier therefor. 